Immune checkpoint inhibitors in NSCLC

Rolf StahelUniversity Hospital of Zürich

1 |

Zürich, November 3, 2017

What can we learn from the clinical experience of second line immunotherapy of advanced NSCLC?

• The observation of durable remissions in patients with metastatic NSCLC progressing after chemotherapy suggests a small proportion of patients might be cured by single agent immune checkpoint inhibition

• Second line therapy with single agent immune checkpoint inhibitors (nivolumab, pembrolizumab or atezolizumab):

• Provides a survival advantage over chemotherapy• Is associated with fewer side effects and better quality of life

• The optimal duration of treatment in patients responding to immune checkpoint inhibitors remains to be determined

• There is potential in the combination with with radiotherapy

• Immune checkpoint inhibitors have activity against CNS metastases

2 |

Five-year follow-up from the CA209-003 study of nivolumabin previously treated advanced NSCLC: Overall survival

3 |

Median OS (95% CI), mo

Overall (N = 129) 9.9 (7.8, 12.4)

100

80

60

40

20

00 1 2 3 4 5 6 7 8

129 49 27 20 17 16 3 1 0

YearsNo. at Risk

OS

(%

)

1 y OS, 42%

2 y OS, 24%3 y OS, 18% 5 y OS, 16%

54% pretreated with 3-5 therapies, 17% confirmed responsesOf the 16 pts surviving 5 years, 12 had a PR, 3 SD and 1 PD as best response

Brahmer, AACR 2017

Five-year follow-up from the CA209-003 study of nivolumabin previously treated advanced NSCLC: Outcome and subsequent treatment of the 16 long term survivors

4 |

• 12/16 patients remain without evidence disease progression

• 4 patients had subsequent therapy

• 1 had surgical resection alone (and remains with no evidence of disease)

• 1 had surgery followed by systemic therapies

• 2 had systemic therapies

Brahmer, AACR 2017

Checkmate 017 and 057: 2-years update of OAS(no biomarker selection)

5 |

Horn, JCO 2017

Checkmate 017 and 057: 2-years update of PFS6 |

Horn, JCO 2017

KEYNOTE 10: Pembrolizumab versus doxetaxel in 2nd lineNSCLC (≥1% of tumor cells PD-L1 positive)

7 |

Herbst, ESMO Asia 2015, Lancet 2016

OAK: A randomized phase III study comparing atezolizumabwith docetaxel in advanced NSCLC

8 |

Barlesi, ESMO 2016

Less toxicity with immune checkpoint inhibitors in second line comparative studies

9 |

ToxicityGade

% of patients

Check-mate 17 Checkmate 57 KEYNOTE 10

N Doc N Doc P2 P10 Doc

All 59 87 69 88 63 66 35

3-5 8 60 10 54 13 16 79

EQ-5D utility index: Mean scores over time while on treatment10 |

Lung Cancer Norm (UK-based): 0.67 b

Mea

n E

Q-5

D U

tility

Inde

x S

core

97 50 32 32 21 18 13 13 8Nivolumab (n = 97)

88 32 9 5 5 4 4 2 1Docetaxel (n = 89)

0 12 24 30 36 42 48 54 60

1.0

0.9

0.8

0.7

0.6

0.5

0.4

Population Norm a

DocetaxelNivolumab

Higher scores indicate better health status.Only time points that had PRO data available for ≥5 patients in either treatment arm are plotted on the graph.

Week

Reck, ECCO-ESMO 2015

Association between immune-related side effects and better outcome?

• June 2015: Pleomorphic carcinoma RUL, with nodal and bone metastases

• July-August 2015: Chemotherapy

• September 2015: Progressive disease, palliative RUL resection

11 |

09/2015RT, followed by 2 cycles of nivolumab, stopped because of pneumonitis

11/2015 03/2017

Safety of retreatment with immune checkpoint inhibitors after treatment related toxicity?

12 |

Santini, ASCO 2017

• 2 treatment-related deaths due to pneumonitis and colitis

• 8% (3/38) objective responses

38 patients receiving renewed treatment after interruption because of immune related adverse event:

CheckMate 153: Randomized results of continuous vs 1-Year fixed-duration nivolumab in patients with advanced NSCLC

13 |

Spigel, ESMO 2017

CheckMate 153: Randomized results of continuous vs 1-Year fixed-duration nivolumab in patients with advanced NSCLC

14 |

Spigel, ESMO 2017

PFS from randomization OS from randomization

CheckMate 153: Randomized results of continuous vs 1-Year fixed-duration nivolumab in patients with advanced NSCLC

15 |

Spigel, ESMO 2017

PFS from randomization

Previous radiotherapy and the clinical activity of pembrolizumab in the treatment of NSCLC: A secondary analysis of the KEYNOTE-001 phase 1 trial

16 |

Shaverdian, Lancet Oncol 2017

Pembrolizumab for patients with melanoma or NSCLC anduntreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial

17 |

Goldberg, Lancet Oncol 2016

Intracranial response to nivolumab in NSCLC patients withuntreated or progressing CNS metastases

• 5 patients: 1 CR 1 PR to nivolumab alone

18 |

Dudnik, Lung Cancer 2016

What can we learn from the biomarker experience of immunotherapy of advanced NSCLC?

• PD-L1 expression is an – albeit imperfect - biomarker with predictive value in advanced NSCLC

• There is a relationship between the neo-antigen load an the likelihood of response to immune checkpoint inhibition

• Clonal neo-antigens, but not subclonal neo-antigens, are associated with durable clinical benefit

• Tumor mutation load is likely to be come next biomarker introduced in clinical practice

• EGFR muted and ALK rearranged NSCLC have a low mutation burden and are not good candidates for immunotherapy

19 |

A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in NSCLC

20 |

Rimm, JAMO Oncol 2017

28-8 antibody on the Dako Link 48 platform22c3 antibody on the Dako Link 48 platformSP142 antibody on the Ventana Benchmark platform, E1L3N antibody on the Leica Bond platform

Relationship of PD-L1 expression and outcome21 |

KEYNOTE 10: Pembrolizumab versus doxetaxel in 2nd line NSCLC (≥1% of

tumor cells PD-L1 positive)

OAK: A randomized phase III study comparing atezolizumab with docetaxel

in advanced NSCLCBarlesi, ESMO 2016Baas, ASCO 2016

Relationship of PD-L1 expression and outcome22 |

KEYNOTE 10: Pembrolizumab versus doxetaxel in 2nd line NSCLC (≥1% of

tumor cells PD-L1 positive)

OAK: A randomized phase III study comparing atezolizumab with docetaxel

in advanced NSCLCBarlesi, ESMO 2016Baas, ASCO 2016

Poplar: T-effector and interferon signature23 |

Fehrenbacher, Lancert Oncol 2016

Mutational load and outcome of immune checkpoint inhibitor therapies in NSCLC

24 |

Rizvi, Science 2015; McGranaham, Science 2016

DBC: Durable clinical benefit; NBC: No durable clinical benefit

Impact of tumor mutation burden on the efficacy of first-line nivolumabin advanced NSCLC: PFS by TMB subgroup and PD-L1 expression

25 |

32 24 13 12 7 5 2 1

28 18 9 3 2 2 2 0

53 35 23 13 10 8 3 0

41 30 14 10 5 4 2 0

No. at RiskHigh TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 ≥50%

16 13 10 8 8 6 2 0 0

31 17 16 13 8 6 2 1 0

70 33 18 9 7 5 1 1 1

41 21 12 6 2 2 1 0 0

Months

100

75

50

25

0

6 18930 12 15 21

Months

100

75

50

25

0

6 1893

PF

S (

%)

0 12 15 2421

High TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 1–49%

Low/medium TMB, PD-L1 ≥50%

Low/medium TMB, PD-L1 ≥50%

High TMB, PD-L1 1–49%

Low/medium TMB,

PD-L1 1–49%

High TMB, PD-L1 ≥50%

Nivolumab Arm Chemotherapy Arm

Peters, AACR 2017

Tumor mutational burden in blood is associated with improved atezolizumab efficacy in 2L+ NSCLC (POPLAR and OAK)

26 |

Gandara, ESMO 2016

Checkpoint inhibitors in metastatic EGFR-mutated NSCLC-a meta-analysis

27 |

Lee, JTO 2017

What are the developments using immune checkpoint inhibitors is first line

• The response rate with single immune checkpoint inhibitions in unselected patients is lower as standard chemotherapy

• Pembrolizumab has been approved as first line treatment for patients with NSCLC expression PD-L1 in 50% or more of tumor cells

• Combinations inhibitors of the PD-1/PD-1 axis with chemotherapy or CTLA-4 inhibitors show encouraging results in unselected patients

• The use of immune checkpoint inhibitors in earlier stages of disease (neoadjuvant, consolidation after radio-chemotherapy, adjuvant after complete resection) is under investigations

28 |

ORR by PD-L1 expression levels in first line NSCLC with single agent PD-1 or PD-L1 directed antibody

29 |

OR

R (

%)

CheckMate 012 KN-001 BIRCH JAVELIN Solid TumorDurva(NCT01693562)

5044

28

14

23

58.3

17.410

2619

29

11

27

15.421.420

0

18.7

50

12.2

0

10

20

30

40

50

60

PD-L1 Cutoffs:

29

30 | Phase 3 PD1/PD-L1 inhibition in 1L advanced NSCLC

Durvalumab

MYSTIC

Atezolizumab

Impower 110

An

ti-P

D-1

/PD

-L1

Nivolumab

CHECKMATE 227

Primary endpoints:

OS, PFS

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Treatment-naïve or recurrent NSCLC

N=1980

Atezolizumab

Gemcitabine + cisplatin or carboplatin

Primary endpoint:

PFS

Stage IV squamous PD-L1+ NSCLC

N=400

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint:

PFSAtezolizumab + bevacizumab + paclitaxel +

carboplatinStage IV non-squamous NSCLC

N=1200

Atezolizumab + carboplatin

+ nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint:

PFSStage IV non-squamous NSCLC

N=550

Atezolizumab

Carboplatin or carboplatin + pemetrexed

Primary endpoint:

PFSStage IV non-squamous PD-L1+ NSCLC N=400

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint:

PFSAtezolizumab + carboplatin + paclitaxel

Stage IV squamous NSCLC

N=1200

Primary endpoint:

PFS and OS

Durvalumab

Durvalumab + tremelimumab

SOC chemotherapy

Advanced NSCLC

N=675

Durvalumab

NEPTUNEDurvalumab + Tremelimumab

SOC chemotherapy

Primary endpoint:

OSFirst-line metastatic NSCLC

N=800

Atezolizumab

Impower 111

Atezolizumab

Impower 130

Atezolizumab

Impower 131

Atezolizumab

Impower 150

Pembrolizumab

KEYNOTE-189Primary endpoints:

PFS

Pembrolizumab + pemetrexed/platinum

Pemetrexed/platinum

Treatment-naïve non-squamous NSCLC

N=580

Nivolumab

CHECKMATE 026

Nivolumab 3 mg/kg IV Q2W

ICCa with potential for crossover

Primary endpoint:

PFS

Treatment-naïve non-squamous NSCLC

PD-L1–positive NSCLC

N=495

Pembrolizumab

KEYNOTE-042

Pembrolizumab 200 mg IV Q3W

SOC chemotherapy

Treatment-naïve non-squamous NSCLC

PD-L1–positive NSCLC

N=1240

Primary endpoint:

OSICCa with potential for crossover

Pembrolizumab

KEYNOTE-024

Pembrolizumab 200 mg IV Q3W

Platin-based chemotherapy

Treatment-naïve non-squamous NSCLC

PD-L1–positive NSCLC

N=305

Primary endpoint:

OS

Neg. PFS

Pos. OS

Neg. PFS, OS pending

CheckMate 026: A phase 3 trial of nivolumab vs investigator's choice of platinum-based doublet chemotherapy as first-line therapy for stage IV/recurrent PD-L1 positive NSCLC

31 |

Socinski, ESMO 2016

KEYNOTE-024: Pembrolizumab vs platinum-basedchemotherapy as first-Line therapy for advanced NSCLC witha PD-L1 TPS ≥50%

32 |

Reck, ESMO 2016

KEYNOTE-024: Pembrolizumab vs platinum-basedchemotherapy as first-Line therapy for advanced NSCLC witha PD-L1 TPS ≥50%

33 |

Reck, ESMO 2016 and NEJM 2016

KEYNOTE-024: Pembrolizumab vs platinum-basedchemotherapy as for advanced NSCLC Updated results

34 |

Brahmer, WCLC 2017

KEYNOTE-024: Pembrolizumab vs platinum-basedchemotherapy for advanced NSCLC: Updated results

35 |

Brahmer, WCLC 2017

KEYNOTE-024: Pembrolizumab vs platinum-basedchemotherapy for advanced NSCLC: Updated results

36 |

Brahmer, WCLC 2017

37 |

Combination therapies: Early results in first line therapy of advanced NSCLC

38 |

Randomized phase-2 study of first linechemotherapy with or without pembrolizumab (no restriction regarding PD-L1 expression)

NSCLC cohorts treated in first line with nivolumab alone or nivolumab combined with

ipililumab according to PD-L1 expression

Langer, Lancet Oncol 2016 Hellmann, Lancet Oncol 2016

Phase III KEYNOTE-189 CheckMate 227

Randomized phase-2 study of carboplatin and pemetexed with orwithout pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G: Updated results

39 |

Borghaei, ESMO2017

Randomized phase-2 study of carboplatin and pemetexed with orwithout pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G: Updated results

40 |

Borghaei, ESMO2017

Updated Results From KEYNOTE-021 Cohort G41 |

Borghaei, ESMO2017

Neoadjuvant nivolumab in early stage resectable NSCLC42 |

Histopathologic Response (N=17)*(% residual viable tumor)

%

<10% 38

10-50% 13

>50% 50

*Only resected patients included for histopathologic response and downstaging exploratory analyses

Pathologic downstagingfrom Pre-treatment Clinical Stage (N=17)*

%

Yes 39

No 61

Forde, ESMO 2016

Pre-

nivo

Post-

nivo

63yo M, ex-smoker, adeno, PD-L1 2%+,

<10% viable tumor at resection

Pre-

nivo

Post-

nivo

NICOLAS - A feasibility trial evaluating nivolumab consolidation after standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC (amendment 1)

43 |

ETOP | Ongoing ETOP Trials | Roche Scientific Meeting | Zurich, 16 March 2017

Study design:Multicentre, single-arm phase II trial. ETOP sponsored

Primary Endpoint:• Grade ≥3 pneumonitis

Sample Size:• 43 patients

Screening, eligibility and enrolment

Nivolumab:480mg Q4W up to 1 year

Stage IIIA / BNSCLC

chemo cycle 1

chemo cycle 2

chemo cycle 3 Radiotherapy

Radiotherapy

chemo cycle 3

chemo cycle 1

chemo cycle 2

Investi-gator‘s choice

• • • until PD

Whole body FDG-PET

CT scans year 1 : every 9 weeks, year 2 : every 12 weeks, beyond 2 years : every 6 months

Nivolumab: 360 mg Q3W, 4 doses

Nivolumab: 240mg Q2W, 8 doses

PACIFIC: Consolidation durvalumab for 1 year after chemo-radiotherapy of stage III NSCLC

• 713 pts with stage III NSCLC after chemo-radiotherapy

• 2:1 durvalumab 10 mg/kg Q2w for 12 months or placebo

44 |

Paz-Ares, ESMO 2017; Antonia, NEJM 2017

45 | PEARLS: Pembrolizumab adjuvant therapy after complete resection of stages IB-IIIA NSCLC

Study design:Multicentre, randomized, placebo controlled phase III trial. - MSD sponsored- EORTC coordinated- ETOP as collaborative group

Co-primary endpoint:• DFS in the PD-L1 strong sub-group• DFS in the overall population

Sample Size:• 1380 randomized patients

46 |

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009